chr19-38477708-A-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_000540.3(RYR1):c.4294-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000540.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.4294-2A>G | splice_acceptor_variant | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.4294-2A>G | splice_acceptor_variant | 5 | NM_000540.3 | A2 | |||
RYR1 | ENST00000355481.8 | c.4294-2A>G | splice_acceptor_variant | 1 | P4 | ||||
RYR1 | ENST00000599547.6 | c.4294-2A>G | splice_acceptor_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461856Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727236
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
RYR1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 27, 2017 | This sequence change affects an acceptor splice site in intron 29 of the RYR1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RYR1-related disease. In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and typically loss-of-function variants in RYR1 are known to cause autosomal recessive RYR1-related disorders (PMID: 23919265). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at